This invention relates to fused heterocyclic carboxamides, for example, N-(2,2-diphenylethenyl)-3-hydroxythieno[3,2-b]thiophene-2-carboxamide.
These novel compounds are found to be effective cyclooxygenase and 5-lipoxygenase inhibitors and are therefore useful in the treatment of inflammation and other prostaglandins and/or leukotriene mediated diseases.
Among various potent biological mediators derived from the oxygenation of arachidonic acid, prostaglandins and leukotrienes have been linked to various diseases. Notably, the biosynthesis of prostaglandins has been identified as a cause of inflammation, arthritic conditions (e.g., rheumatoid arthritis, osteoarthritis and gout), psoriasis, inflammatory bowel disease, and pain. Furthermore, the formation of leukotrienes has been connected to immediate hypersensitivity reactions and proinflammatory effects. It has been established that arachidonic acid undergoes oxygenation via two major enzymatic pathways:
(1) The pathway catalyzed by the enzyme cyclooxygenase; and PA1 (2) The pathway catalyzed by the enzyme 5-lipoxygenase. PA1 (a) H; PA1 (b) loweralkyl, especially C.sub.1-6 alkyl such as methyl, ethyl, i-propyl, n-propyl, t-butyl, n-butyl, i-pentyl, n-pentyl and n-hexyl; PA1 (c) aryl especially C.sub.6-14 aryl e.g., naphthyl, anthryl, phenyl or substituted phenyl of formula ##STR2## wherein X.sub.5 and X.sub.6 independently are: 1) Q, where Q is H, loweralkyl especially C.sub.1-6 alkyl, haloloweralkyl especially fluoro or chloro C.sub.1-6 alkyl such as trifluoromethyl, phenyl or substituted phenyl, or naphthyl; PA1 (d) lowercycloalkyl especially C.sub.3-6 cycloalkyl, e.g., cyclopropyl, cyclopentyl and cyclohexyl; PA1 (e) haloloweralkyl especially halo C.sub.1-6 alkyl, e.g. CF.sub.3 --, CHF.sub.2 --, C.sub.2 F.sub.5 --; PA1 (f) heteroaryl or heteroaryl substituted with X.sub.5 and X.sub.6 especially pyridyl, pyrryl, furyl or thienyl wherein X.sub.5 and X.sub.6 are as previously defined; PA1 (g) benzyl or substituted benzyl of formula ##STR3## wherein X.sub.5 and X.sub.6 are as previously defined; (h) loweralkynyl especially C.sub.1-6 alkynyl such as --C.tbd.CH; CH.sub.3 --C.tbd.C--, or HC.tbd.C--CH.sub.2 --; PA1 (i) loweralkynyl especially C.sub.1-6 alkenyl, such as CH.sub.2 .dbd.CH--, CH.sub.3 CH.dbd.CH--, CH.sub.2 .dbd.CHCH.sub.2 --, CH.sub.3 CH.dbd.CH--CH.sub.2 -- or (CH.sub.3).sub.2 C.dbd.CH; PA1 (j) phenylloweralkenyl of formula ##STR4## where X.sub.5 and X.sub.6 are as previously defined; or (k) phenylloweralkynyl of formula ##STR5## where X.sub.5 and X.sub.6 are as previously defined; (1) ##STR6## wherein R.sup.5 is R; ##STR7## PA1 (a) R as previously defined; or PA1 (b) X.sub.5 ; PA1 (a) R; or PA1 (b) R.sup.2 and R.sup.3 joined together forming a ring of structure ##STR9## wherein X.sub.5 and X.sub.6 are as previously defined and Y is (CH.sub.2).sub.n, O, S, SO, SO.sub.2, NQ; or PA1 (c) halo; PA1 (a) R; or PA1 (b) --CR.sup.1 .dbd.CR.sup.2 R.sup.3 ; PA1 (a) H; PA1 (b) loweralkyl; PA1 (c) haloloweralkyl especially halo-C.sub.1-6 alkyl such as CF.sub.3 ; or PA1 (d) halo; and PA1 (a) loweralkyl; PA1 (b) phenyl or substituted phenyl; PA1 (c) heteroaryl or substituted heteroaryl especially thienyl, furyl or pyrryl; and
Interruption of these pathways by enzyme inhibition has been explored for effective therapy. For example, non-steroidal anti-inflammatory drugs (NSAID) such as aspirin, indomethacin and diflunisal are known cyclooxygenase inhibitors which inhibit the process wherein arachidonic acid is oxygenated via cyclooxygenase to prostaglandins and thromboxanes.
Recently, it has been observed that certain leukotrienes are responsible for diseases related to immediate hypersensitivity reactions such as human asthma, allergic disorders, and skin diseases. In addition, certain leukotrienes and derivatives thereof are believed to play an important role in causing inflammation (B. Samuelsson, Science, 220, 568 (1983); D. Bailey et al, Ann. Rpts. Med. Chem., 17, 203 (1982)).
Through recent research, 5-lipoxygenase inhibitors has been linked to the treatment of eye inflammation and used as cytoprotective agents.
To be an effective and acceptable topical agent for treating eye inflammation, a drug must not only penetrate the ophthalmic tissues to reach the active sites within the eye, but it must also be devoid of those side effects including irritation, allergic reaction and the like which would militate against long term administration.
With respect to the cytoprotective activity, it has been known that (1) gastric cytoprotection does not involve inhibition of gastric acid secretion. For example, protaglandin F2B does not inhibit gastric acid secretion, but it does induce gastric cytoprotection (S. Szabo et al., Experimentia, 38, 254, 1982); (2) lower effective dosages of cyto-protective agents are required than that of gastric acid inhibitors; and (3) the cytoprotective activity of a compound may be observed in both animals and man by noting the increased resistance of gastrointestinal mucosa to strong irritants. For example, animal studies have shown that cytoprotective compounds will prevent gastric lesions induced by oral administration of strong acids, strong bases, ethanol, hypertonic saline, etc.